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PUBLIC RELEASE DATE:
20-Oct-2013

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Contact: Lauren Riley
lauren.riley@aacr.org
215-446-7109
American Association for Cancer Research

New idea for targeting the common cancer protein KRAS

BOSTON Patients with cancers driven by the protein KRAS, which are particularly hard to treat, may benefit from small molecules that attach to and disrupt the function of a KRAS-containing protein complex, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.

Mutant forms of the protein KRAS are found in approximately 30 percent of all cancers. They are responsible for many of the hallmarks of these cancers, and KRAS is, therefore, considered an important therapeutic target. However, attempts to develop clinically useful KRAS-targeted drugs have been unsuccessful.

"KRAS is a molecular switch," said Michael Burns, a doctor of medicine and doctor of philosophy candidate at Vanderbilt School of Medicine in Nashville, Tenn. "In the 'on' state it transmits signals that drive cell growth and survival. In many cancers, KRAS is permanently in the on state, and it is a highly validated therapeutic target.

"KRAS switches from off to on most efficiently when it is attached to a protein called SOS," explained Burns. "Each SOS protein attaches to two KRAS proteins, and we have identified a number of small molecules that bind to a particular part of SOS when it is in a complex with two KRAS proteins. These small molecules disrupt the function of the complex, ultimately causing inhibition of the signaling pathways downstream of KRAS that drive cell growth and survival. Although our data were generated in biochemical assays and cell lines, they suggest a potential way to therapeutically target KRAS, which has not been possible to date."

KRAS switches from off to on during a process called guanine nucleotide exchange, and SOS increases the rate at which this process occurs. Burns and colleagues hypothesized that small molecules that blocked SOS-mediated guanine nucleotide exchange would prevent KRAS switching on and, therefore, inhibit the signaling pathways downstream of KRAS that drive cell growth and survival.

Instead, they found that a number of small molecules that attached to a special pocket in a region of SOS called the CDC25 domain and increased SOS-mediated guanine nucleotide exchange actually inhibited two of the major signaling pathways downstream of KRAS: the MAPK and PI3K signaling pathways.

The researchers are actively investigating why small molecules that increased SOS-mediated guanine nucleotide exchange in biochemical assays blocked signaling downstream of KRAS in cell lines. They are also working to optimize the small molecules before they conduct studies in preclinical models of cancer.

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This study was funded by an Ann Melly Scholarship in Oncology, the Vanderbilt Medical Training Program, the National Institutes of Health, and the Lustgarten Foundation. Burns has no conflicts of interest to declare.

The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).

This research will be presented at a press conference entitled "Emerging Therapeutics" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Sunday, Oct. 20 at 10 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:

To interview Michael Burns, contact Dagny Stuart at dagny.stuart@vanderbilt.edu or 615-936-7245. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.

About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.

About the National Cancer Institute

The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

About the European Organisation for Research and Treatment of Cancer

The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.

EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org

Abstract Number: C209/PR01
Presenter: Michael Burns

Title: Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange

Authors: Michael Burns1, Qi Sun1, Richard Daniels2, J. Phillip Kennedy1, DeMarco Camper1, Jason Phan1, Edward Olejniczak1, Taekyu Lee1, Alex Waterson1, Olivia Rossanese1, Stephen Fesik1. 1Vanderbilt University School of Medicine, Nashville, TN; 2Lipscomb University, Nashville, TN

Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active receptor tyrosine kinases (RTKs) results in the deregulation of cellular signals governing growth and survival in cancer. The guanine nucleotide exchange factor Son of Sevenless (SOS) catalyzes the rate-limiting step in the activation of Ras by exchanging GDP for GTP. SOS is therefore a key control point for the propagation of RTK and Ras signaling. Here we report the discovery of small molecules that bind to a unique pocket on the Ras:SOS:Ras complex, increase SOScat-catalyzed nucleotide exchange, and perturb Ras signaling pathways in cells. X-ray crystallographic studies of Ras:SOS:Ras complexed with these small molecules reveal that they bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of the x-ray structures of multiple co-complexes. In addition, structure-based mutational analyses indicate that this newly identified pocket is essential for compound activity. As predicted, these molecules increase Ras-GTP levels in cells. However, they unexpectedly inhibit MAPK and PI3K signaling. Our studies suggest a novel way to target K-Ras and offer possible starting points for the discovery of compounds that could be used to treat Ras-driven tumors.



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